AMERICAN ASSOCIATION OF NEUROMUSCULAR & ELECTRODIAGNOSTIC MEDICINE

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1 AMERICAN ASSOCIATION OF NEUROMUSCULAR & ELECTRODIAGNOSTIC MEDICINE Charcot-Marie-Tooth This course/handout is sponsored by the Hereditary Neuropathy Foundation through an agreement with the Centers for Disease Control and Prevention. (1U38DD ) Photo by Michael D. Stubblefi eld, MD

2 Charcot-Marie-Tooth Robert M. Bernstein, MD Robert D. Chetlin, PhD, CSCS, CHFS Mitchell Warner, CPO Hal Ornstein, DPM, FASPS reviewed and accepted by the Program Committee of the american association of neuromuscular & electrodiagnostic Medicine Designated for CME credit 09/ /2020. Reviewed and renewed 10/14 and 11/17 AANEM 58th Annual Meeting San Francisco, California Copyright September 2011 American Association of Neuromuscular & Electrodiagnostic Medicine 2621 Superior Drive NW Rochester, MN Printed by Johnson s Printing Company, Inc. 1

3 Please be aware that some of the medical devices or pharmaceuticals discussed in this handout may not be cleared by the FDA or cleared by the FDA for the specific use described by the authors and are off-label (i.e., a use not described on the product s label). Off-label devices or pharmaceuticals may be used if, in the judgment of the treating physician, such use is medically indicated to treat a patient s condition. Information regarding the FDA clearance status of a particular device or pharmaceutical may be obtained by reading the product s package labeling, by contacting a sales representative or legal counsel of the manufacturer of the device or pharmaceutical, or by contacting the FDA at

4 Charcot-Marie-Tooth Table of Contents Course Objectives & Course Committee 4 Faculty 5 Pediatric Orthopaedic Surgery and the Hereditary Motor Sensory Neuropathies 7 Robert M. Bernstein, MD Contemporary Treatment and Management of Charcot-Marie-Tooth Disease: Embracing the Exercise Is Medicine Model 13 Robert D. Chetlin, PhD, CSCS, CHFS Corrective Lower Limb Bracing in Charcot-Marie-Tooth Disease 19 Mitchell Warner, CPO Charcot-Marie-Tooth Disease: Current Topics and Treatment Options in Podiatric Medicine and Surgery 23 Hal Ornstein, DPM, FASPS CME Questions 27 No one involved in the planning of this CME activity had any relevant financial relationships to disclose. Authors/faculty have nothing to disclose. Course Chairs: Pragna Patel, PhD and David Pleasure, MD The ideas and opinions expressed in this publication are solely those of the specific authors and do not necessarily represent those of the AANEM. 3

5 Objectives Objectives - Participants will acquire skills to (1) diagnose CMT based on common symptomology; (2) discuss work-up and surgical treatment options for the very young to adults; (3) identify the potential benefits of occupational and physical therapies and bracing to help normalize life for those diagnosed and their care-givers. Target Audience: Neurologists, physical medicine and rehabilitation and other physicians interested in neuromuscular and electrodiagnostic medicine Health care professionals involved in the management of patients with neuromuscular diseases Researchers who are actively involved in the neuromuscular and/or electrodiagnostic research Accreditation Statement - The AANEM is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. CME Credit - The AANEM designates this live activity for a maximum of 3.25 AMA PRA Category 1 Credits TM. If purchased, the AANEM designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits TM. This educational event is approved as an Accredited Group Learning Activity under Section 1 of the Framework of Continuing Professional Development (CPD) options for the Maintenance of Certification Program of the Royal College of Physicians and Surgeons of Canada. Physicians should claim only the credit commensurate with the extent of their participation in the activity. CME for this course is available 09/ /20. CEUs Credit - The AANEM has designated this live activity for a maximum of 3.25 AANEM CEUs. If purchased, the AANEM designates this enduring material for a maximum of 1.5 CEUs Course Committee Shawn J. Bird, MD, Chair Philadelphia, PA Gary L. Branch, DO Owosso, MI Lawrence W. Frank, MD Elmhurst, IL Taylor B. Harrison, MD Atlanta, GA Laurence J. Kinsella, MD Saint Louis, MO Shashi B. Kumar, MD Tacoma, WA A. Arturo Leis, MD Jackson, MS Marcy C. Schlinger, DO Okemos, MI Benjamin S. Warfel, MD Lancaster, PA AANEM President Timothy R. Dillingham, MD, MS Milwaukee, Wisconsin 4

6 Charcot-Marie-Tooth Robert M. Bernstein, MD Chief, Pediatric Orthopaedic Surgery and Rehabilitation Steven & Alexandra Cohen Children s Medical Center of New York Associate Professor of Orthopaedics and Pediatrics Hofstra/North Shore/LIJ School of Medicine New York, New York Dr. Bernstein received his medical degree from the University of Southern California, School of Medicine. He completed his internship at the University of South Florida. Dr. Bernstein then completed his orthopaedic residency at the Harvard Combined Orthopaedic Residency Program at the Massachusetts General Hospital. He also completed a fellowship in pediatric orthopaedics at Children s Hospital in Boston and a fellowship in spine surgery at Beth Israel Hospital in Boston. Board certified in orthopedics, Dr. Bernstein is internationally recognized as an expert in the areas of scoliosis and spinal deformity, hip dysplasia, clubfeet, children s fractures, limb lengthening, children with limb deficiencies, arthrogryposis and other skeletal dysplasias. He is actively involved in global health and developed a program called Mobile Pediatric Orthopaedic Education which teaches sustainable orthopaedic surgery for children in the developing world. Dr. Bernstein s research findings have been published in several peer-reviewed journals including the Journal of Bone and Joint Surgery, Journal of the American Academy of Orthopedic Surgery, Journal of Pediatric Orthopaedics, Spine, Journal of Orthopedic Trauma, Current Opinion in Orthopaedics, and the American Journal of Orthopaedics. In addition, Dr. Bernstein has written a number of chapters for various orthopedic textbooks and has lectured internationally. Dr. Bernstein is a member of the American Academy of Orthopedic Surgeons, the Pediatric Orthopaedic Society of North America, the Scoliosis Research Society, and the Association of Children s Prosthetic and Orthotics Clinics. Faculty Robert D. Chetlin, PhD, CSCS, CHFS Associate Professor Department of Human Performance & Applied Exercise Science Department of Neurology West Virginia University School of Medicine Morgantown, West Virginia Dr. Chetlin is an exercise physiologist in the West Virginia University School of Medicine, where he holds a dual appointment as an associate professor in the Department of Human Performance & Applied Exercise Science and the Department of Neurology. Dr. Chetlin is a professional member of the American College of Sports Medicine (ACSM) and the National Strength and Conditioning Association (NSCA). He holds professional accreditation as a Certified Health Fitness Specialist through ACSM and as a Certified Strength and Conditioning Specialist through NSCA. Dr. Chetlin s research interests involve investigating the effects of exercise and activity training, nutritional supplements, and pharmaceuticals in adult and pediatric patients with a variety of neuromuscular disorders, specifically Charcot-Marie-Tooth (CMT) disease. He has published his work in several peerreviewed research journals, including Muscle & Nerve, Archives of Clinical Medicine and Rehabilitation, and Medicine and Science in Sports and Exercise. Dr. Chetlin currently is preparing to examine a novel model of bidirectional translational research, which will investigate the effects of exercise training and neurotrophic drugs in the treatment of CMT disease. In 2004, Dr. Chetlin was recognized for his contribution to improving the lives of patients with peripheral neuropathy when he received The CMT Foundation Award for Distinguished Service. 5

7 Hal Ornstein, DPM, FASPS Medical Director Affiliated Foot and Ankle Center, LLP Howell, New Jersey Dr. Ornstein serves as chairman and director of corporate development for the American Academy of Podiatric Practice Management, consulting editor for Podiatry Management Magazine, and faculty and coordinator of the 4-year practice management course at the Ohio College of Podiatric Medicine. He is a Distinguished Practitioner in the National Academies of Practice in Podiatry, has given over 250 presentations internationally, and has written and been interviewed for more than 300 articles on topics pertinent to practice management, patient satisfaction, and efficiency in a medical practice. In 2009, he was inducted into the Podiatric Hall of Fame and received the Podiatry Management Magazine Lifetime Achievement Award. He is coauthor of a multidisciplinary management text entitled 37-1/2 Essential Tips for Practice Management Success. Dr. Ornstein has been in private practice for over 20 years. Mitchell Warner, CPO Certified Prosthetist and Orthotist Ortho Rehab Designs Prosthetics and Orthotics Inc. Las Vegas, Nevada Mr. Warner founded Ortho Rehab Designs Prosthetics and Orthotics Inc. in April of The fields of orthotics and prosthetics enable him to use his education and skills to help patients lead more normal lives. Currently, Mr. Mitchell has a full and thriving practice and sees patients from all over the world for his lower limb orthoses. He has been treating patients for the last 23 years in private clinical practice, hospitals, rehabilitation centers, and the Veterans Administration. Mr. Mitchell graduated from the New York University Post-Graduate Medical School s program in orthotics and prosthetics and is board certified in both prosthetics and orthotics. He has lectured extensively to physicians, physical therapy groups, hospitals, and patient support groups, addressing floor reaction applications designed to correct deformity. He is currently involved in research and development of carbon graphite applications and design in both prosthetics and orthotics. 6

8 Pediatric Orthopaedic Surgery and the Hereditary Motor Sensory Neuropathies Robert M. Bernstein, MD Chief, Pediatric Orthopaedic Surgery and Rehabilitation Steven & Alexandra Cohen Children s Medical Center of New York Associate Professor of Orthopaedics and Pediatrics Hofstra/North Shore/LIJ School of Medicine New York, New York INTRODUCTION The hereditary motor sensory neuropathies (HMSNs) are comprised of numerous diseases that result in abnormal peripheral nerve function. The most common is Charcot-Marie-Tooth (CMT) disease. These disorders have orthopedic problems and present with weakness, gait abnormalities, sensory loss, and progressive deformities. As with any disease, an understanding of the natural history is important to determine effective treatment. Because most of the HMSNs have only now been delineated by specific genetic markers, the orthopedic literature regarding diagnosis and treatment of specific HMSNs is scant and primarily descriptive, with few articles containing meaningful numbers of patients. Because CMT1a is the most common type of HMSN, more information has been published about it than the other diseases. Thus, CMT1a will be the primary focus of this discussion. However, many of the orthopedic manifestations are similar throughout this family of diseases, and many of the lessons from CMT1a can be extrapolated (out of necessity) to the less common forms of HMSN. Early Recognition of Disease Because HMSNs are chronic and progressive neuropathies, patients will experience a progression of symptoms. Initially, children may not complain of any noticeable weakness or deformity. Pes valgus and lack of reflexes may be the earliest signs. 1 However, it should be remembered that pes valgus is a normal variant in the general population. The parents may also notice an ungainly gait and a lack of coordination in their child. Again, these are very nonspecific findings. As peripheral weakness progresses, the child will gradually develop the more commonly recognized signs of CMT, including intrinsic wasting of the hands, cavus foot deformities, and claw toes. 2 The gait abnormality becomes more obvious, often with development of a drop foot resulting in a steppage type gait. Accentuation of pelvic tilt to assist in clearance of the foot has been described as a marionette gait. 3 Equinus contractures may develop as the gastrocnemius muscle overcomes the tibialis anterior and accessory ankle dorsiflexion muscles. Increased use of the accessory dorsiflexors of the foot including the extensor hallucis longus (EHL) and extensor digitorum longus (EDL) result in the development of claw toes. The first metatarsal drops, increasing heel varus and cavus due to a tripod effect. 4 Ankle instability with frequent sprains is a common complaint, as well as the development of metatarsalgia and other foot pain. Eventually, as the cavus deformity becomes fixed, the patient will develop callosities under the first and fifth metatarsal heads and often over the base of the fifth metatarsal as well. Additional orthopaedic problems encountered in CMT population include the development of scoliosis and hip dysplasia. 5,6 The exact pathway by which these problems develop is still unclear. Finally, children with CMT often develop intrinsic weakness of the hands with progressive upper extremity dysfunction and problems with activities of daily living. 7 These upper extremity issues are beyond the scope of this discussion. FOOT DEFORMITIES IN CHILDREN: PREVENTION AND TREATMENT While cavus is considered a sentinel manifestation of disease in children with CMT, some children will have pes valgus and some 7

9 Pediatric Orthopaedic Surgery and the Hereditary Motor Sensory Neuropathies tripping. Different types of braces are available, including the leaf-spring AFO which keeps the foot slightly dorsiflexed but allows slight plantar flexion on heel-strike due to the cutback of material posterior to the ankle joint (Fig. 1). More complicated braces with hinged ankles are also available but provide the same function. Figure 1. Example of a leaf-spring ankle-foot orthosis. will have no foot deformity at all. 8 Limited ankle dorsiflexion, related to Achilles tendon tightness, may be one of the earliest signs. However, over time pes cavus becomes the dominant deformity. 9 Weakness in dorsiflexion resulting in the tight Achilles tendon, accompanied by over pull of the EHL and EDL, results in clawing of the toes and accentuation of the plantar arch as previously discussed. This eventually becomes stiff and a fixed cavovarus deformity results. Once the hindfoot is stiff in varus, correction of the deformity becomes very difficult and triple arthrodesis of the hindfoot to correct this deformity may be the only option to obtain a plantigrade foot. While many patients are happy with the results of triple arthrodesis, there is evidence that its benefits in CMT patients are limited. Eventual degeneration of the surrounding joints of the foot and ankle often result. 10,11 Thus, triple arthrodesis should be reserved for those feet that have severe and rigid deformities (better straight and stiff than deformed and stiff), and every effort should be made to avoid progression to this point. Stretching, Splinting, and Strengthening Given the problems with triple arthrodesis noted above, the goal of treatment in children with CMT is to provide a stable, flexible, plantigrade, pain-free foot that lasts a lifetime and avoids the need for fusion procedures. While there is little evidence of the longterm benefits of stretching, night splinting, and strengthening exercises, 12 there is some published literature supporting stretching and strengthening. 13,14 Importantly, there is little risk to these interventions. Parents often wish to intervene as early as possible, and stretching, splinting, and strengthening are simple, safe modalities that can be employed by the practitioner. Gait Abnormalities and Bracing Associated with the weakness in dorsiflexion are gait abnormalities. Most often, a steppage gait is seen where the patient hyperflexes their hip to avoid catching the toe during the swing phase. Further weakness of the hip flexors may result in overcompensation of pelvic tilt resulting in the marionette gait mentioned above. Simple treatment options include strengthening of the tibialis anterior and the use of an ankle-foot orthosis (AFO) to prevent 8 It is important to remember that the function of a static brace is to hold a joint in a particular position. If the ankle cannot be brought to a neutral position, static bracing will not be possible. Once an equinus contracture has developed, dynamic night bracing may assist in stretching the Achilles tendon. Slight equinus contracture of only a few degrees is well tolerated, particularly since most shoes have a built in angle of plantar flexion. As the equinus worsens, lengthening of the Achilles tendon may be needed to get the foot into a neutral position. Over-lengthening of the Achilles tendon can result in significant weakness of the calf muscles and a calcaneus deformity, with decreased toe off and decreased stride length. In addition, a calcaneus deformity is difficult to brace and may result in significant pain and decreased endurance. Equinus is always better tolerated than calcaneus, so care should be taken never to over-lengthen the Achilles tendon. Tendon Transfers and Osteotomies As weakness and deformity progress, efforts should be made to balance the motors of the foot. Tendon transfers can improve this balance by removing deforming forces and providing more power to weak muscles. There are a number of preconditions to successfully transfer a tendon. Some that are of particular importance to this population include: The muscle to be transferred must be expendable. The muscle must have sufficient strength (grade 4 or greater). In its transferred position the muscle must have action over a mobile joint. It is best to transfer in-faze muscles, if possible. The muscle must have adequate excursion to perform the intended function. In order to determine if the hindfoot is mobile, the Coleman block test is utilized. Plantar flexion of the first metatarsal results in a varus tilt of the heel when the foot is in the standing position (Fig. 2). To establish the presence of mobility of the hindfoot, the patient stands on a block allowing the first metatarsal head to drop off the side of the block. If the heel moves into a valgus position, the hindfoot is flexible. If the hindfoot remains in varus, the deformity is rigid and transfers with osteotomies are likely to fail. Muscles that frequently can be transferred in patients with CMT include the EHL to the first metatarsal (often in conjunction with a first interphalangeal fusion, known as a Jones transfer), the EDL of the lesser toes to the metatarsals (a Girdlestone-Taylor transfer), or the EDL of the lesser toes to the dorsum of the foot (a Hibbs transfer). These transfers improve strength by decreasing wasted motion across the interphalangeal joints as well as removing a deforming force. In addition, one can transfer the peroneus longus to the peroneus brevis to increase eversion strength and decrease

10 plantar flexion of the first ray. The decision to transfer any of these muscles is dependant on those preconditions noted above and the severity of the deformity. Charcot-Marie-Tooth Osteotomies often are included when transferring tendons in order to realign the foot. The two most frequent osteotomies are the Priddie osteotomy (also known as the Koutsogiannis osteotomy), in which the heel is pushed into valgus in order to move the point of heel strike laterally, and a first metatarsal dorsiflexion osteotomy to lift the great toe (Fig. 3). Standing anteroposterior and lateral radiographs of the foot give a fair evaluation of the cavus deformity, but they do not show the position of the heel in stance. The Cobey view is very useful in that it allows determination of the point of contact of the heel in relation to the mechanical axis of the tibia (Fig. 4). B Triple Arthrodesis Finally, in those feet with a rigid hindfoot, triple arthrodesis may be the only option. Wedges of bone from the hindfoot and midfoot may need to be removed in order to realign the foot into a plantigrade position. Early failures of triple arthrodesis are usually the result of under correction. In order to dorsiflex the midfoot, a wedge of bone may need to be removed from the midfoot. Preoperative planning is important and it should be noted that this wedge is a trapezoid. The apex of any wedge taken from the midfoot must be at the plantar surface, as this is the point of rotation, and not at the inferior surface of the bone. Again, while the results of triple arthrodesis are of concern in longterm outcome studies, the operation may be the only option to obtain a plantigrade foot. A Figure 2. The Coleman block test. (A) Fixed deformity: the heel remains in varus after the first metatarsal head drops. (B) Flexible deformity: the heel moves into valgus after the first metatarsal head drops. SCOLIOSIS Scoliosis appears to be more common in the HMSN population than was initially thought. Scoliosis has been documented in 15-37% of patients with CMT, 15,16 and it has been reported in other HMSNs. 17 The most severe deformities seem to occur in Dejerine-Sottas syndrome, with 100% of patients affected in one study. 18 Of CMT patients with scoliosis, 71% of curves were found to progress. Unlike adolescent idiopathic scoliosis, which is usually hypokyphotic, scoliosis associated with CMT may be kyphscoliotic. 5,19 Most curves do not appear to respond to brace treatment 16 but not all require surgical intervention. Figure 3. The Priddie or Koutsogiannis calcaneal osteotomy. The surgical approach for scoliosis associated with CMT is similar to that of the adolescent idiopathic scoliosis population (Fig. 5), with good results reported by Karol and Elerson. 16 They noted that they could only utilize intraoperative somatosensory evoked potentials in 25% of their surgical patients. However, there were no reported neurological deficits postoperatively. HIP DYSPLASIA Hip dysplasia also has been associated with CMT. 6,20 Walker and colleagues noted hip abnormalities in 35% of their patients. Chan and colleagues assumed that the hips of CMT children were normal at birth and that dysplasia develops later. 21 They recommend a standing anteroposterior radiograph of the hip every 2 years, and any infant with known CMT should undergo an ultrasound. The Figure 4. Cobey views of the hindfoot. The line represents the mechanical axis of the tibia. The dot is the lowest point of the heel in stance. This should be in line or lateral to the mechanical axis. 9

11 Pediatric Orthopaedic Surgery and the Hereditary Motor Sensory Neuropathies may delay the onset of cavus deformity in young patients. Early surgery in cavus feet, including tendon transfer and osteotomy to rebalance the foot and correct primary deformity, may prevent patients from later requiring triple arthrodesis. Figure 5. (A) A 15-year-old boy with Charcot-Marie-Tooth disease and a 65 degree thoracic curve. (B) Surgical correction with posterior instrumentation and fusion was uneventful. cause of the hip dysplasia in CMT is unknown but likely is the result of muscle imbalance around the hip. Because of this, it is unclear if nonsurgical means (bracing) can alter the natural history of hip dysplasia in children with CMT. The dysplasia seems to develop later and insidiously. 22,23 Pateints with hip dysplasia may remain asymptomatic for extended periods of time. Due to the variability in disease severity in patients with CMT, age at which hip dysplasia develops also is variable. Generally, surgical intervention to address the acetabular dysplasia by redirectional osteotomy is recommended, with the subsequent addition of intervention on the femoral side if necessary. Proximal femoral varus osteotomy may result in a worsening of gait, so is best performed if the acetabular procedure fails to address all of the dysplasia. Unlike scoliosis treatment in CMT, neurologic dysfunction after hip surgery has been reported, 6,22 so care should be taken not to stretch the peripheral nerves. Chan and colleagues stresses the importance of these patients walking as soon as possible after surgery. 21 CONCLUSIONS The HMSNs are associated with a number of orthopaedic problems including foot deformity, spinal deformity, and hip dysplasia. Young patients may present with flat feet and toe walking. Achilles tendon stretching, dorsiflexor strengthening, and bracing 10 A B Patients with HMSN should be routinely screened for scoliosis by physical examination and for hip dysplasia by radiographs. Bracing may not be successful for patients with scoliosis, but surgery seems to be safe and effective if required. Hip dysplasia may be silent and develop late in childhood and adolescence. Surgery to address the acetabular dysplasia should be performed first, and care should be taken to avoid stretch injury to peripheral nerves. REFERENCES 1. Feasby TE, Hahn AF, Bolton CF, Brown WF, Koopman WJ. Detection of hereditary motor sensory neuropathy type I in childhood. J Neurol Neurosurg Psychiatry 1992;55(10): Sabir M, Lyttle D. Pathogenesis of pes cavus in Charcot-Marie- Tooth disease. Clin Orthop 1983;(175): Sabir M, Lyttle D. Pathogenesis of Charcot-Marie-Tooth disease. Gait analysis and electrophysiologic, genetic, histopathologic, and enzyme studies in a kinship. Clin Orthop 1984;(184): Schwend RM, Drennan JC. Cavus foot deformity in children. J Am Acad Orthop Surg 2003;11(3): Daher YH, Lonstein JE, Winter RB, Bradford DS. Spinal deformities in patients with Charcot-Marie-tooth disease. A review of 12 patients. Clin Orthop 1986;(202): Kumar SJ, Marks HG, Bowen JR, MacEwen GD. Hip dysplasia associated with Charcot-Marie-Tooth disease in the older child and adolescent. J Pediatr Orthop 1985;5(5): Burns J, Bray P, Cross LA, North KN, Ryan MM, Ouvrier RA. Hand involvement in children with Charcot-Marie-Tooth disease type 1A. Neuromuscul Disord 2008;18(12): Wines AP, Chen D, Lynch B, Stephens MM. Foot deformities in children with hereditary motor and sensory neuropathy. J Pediatr Orthop 2005;25(2): Burns J, Ryan MM, Ouvrier RA. Evolution of foot and ankle manifestations in children with CMT1A. Muscle Nerve 2009;39(2): Wetmore RS, Drennan JC. Long-term results of triple arthrodesis in Charcot-Marie-Tooth disease. J Bone Joint Surg Am 1989;71(3): Wukich DK, Bowen JR. A long-term study of triple arthrodesis for correction of pes cavovarus in Charcot-Marie-Tooth disease. J Pediatr Orthop 1989;9(4): Sackley C, Disler PB, Turner-Stokes L, Wade DT. Rehabilitation interventions for foot drop in neuromuscular disease. Cochrane Database Syst Rev 2007(2):CD Burns J, Raymond J, Ouvrier R. Feasibility of foot and ankle strength training in childhood Charcot-Marie-Tooth disease. Neuromuscul Disord 2009;19(12): Rose KJ, Burns J, North KN. Factors associated with foot and ankle strength in healthy preschool-age children and age-matched cases of Charcot-Marie-Tooth disease type 1A. J Child Neurol 2010;25(4): Walker JL, Nelson KR, Stevens DB, Lubicky JP, Ogden JA, VandenBrink KD. Spinal deformity in Charcot-Marie-Tooth disease. Spine 1994;19(9):

12 Charcot-Marie-Tooth 16. Karol LA, Elerson E. Scoliosis in patients with Charcot-Marie- Tooth disease. J Bone Joint Surg Am 2007;89(7): Azzedine H, Ravise N, Verny C, et al. Spine deformities in Charcot- Marie-Tooth 4C caused by SH3TC2 gene mutations. Neurology 2006;67(4): Horacek O, Mazanec R, Morris CE, Kobesova A. Spinal deformities in hereditary motor and sensory neuropathy: a retrospective qualitative, quantitative, genotypical, and familial analysis of 175 patients. Spine. 2007;32(22): Hensinger RN, MacEwen GD. Spinal deformity associated with heritable neurological conditions: spinal muscular atrophy, Friedreich s ataxia, familial dysautonomia, and Charcot-Marie- Tooth disease. J Bone Joint Surg Am 1976;58(1): Fuller JE, DeLuca PA. Acetabular dysplasia and Charcot-Marie- Tooth disease in a family. A report of four cases. J Bone Joint Surg Am 1995;77(7): Chan G, Bowen JR, Kumar SJ. Evaluation and treatment of hip dysplasia in Charcot-Marie-Tooth disease. Orthop Clin N Am 2006;37(2): van Erve RH, Driessen AP. Developmental hip dysplasia in hereditary motor and sensory neuropathy type 1. J Pediatr Orthop 1999;19(1): Bamford NS, White KK, Robinett SA, Otto RK, Gospe SM, Jr. Neuromuscular hip dysplasia in Charcot-Marie-Tooth disease type 1A. Dev Med Child Neurol 2009;51(5):

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14 Contemporary Treatment and Management of Charcot-Marie-Tooth Disease: Embracing the Exercise Is Medicine Model Robert D. Chetlin, PhD, CSCS, CHFS Associate Professor Department of Human Performance & Applied Exercise Science Department of Neurology West Virginia University School of Medicine Morgantown, West Virginia INTRODUCTION Charcot-Marie-Tooth (CMT) disease, also known as hereditary motor and sensory neuropathy (HMSN), is a slow, progressive, peripheral nerve disorder, which, in its most prevalent form (CMT1a, 70% of all CMT type 1 cases), results in muscle atrophy, weakness, and decreased nerve conduction velocity. 5,6,10,13 CMT is the most common inherited peripheral sensorimotor neuropathy, affecting 1 in 2,500 persons. 6,10 The expression of the disease ranges from mild-to-severe, usually with slow progression. Patients with mild symptoms experience varying degrees of distal limb muscle weakness. The weakness is due to a combination of factors, including axonal death due to associated demyelination of peripheral nerves, deconditioning, and disuse atrophy. 5,11,34 A common impairment seen in individuals with CMT is decreased strength in intrinsic foot and lower extremity muscles, especially in the dorsiflexor muscles. 10,34 Weakness also is a concern in the upper extremities, usually to a lesser extent. 5,30 This lower extremity weakness, combined with the disease process of CMT, leads to problems, such as an increased propensity for ankle sprain, abnormal gait, abnormal posturing, and discomfort in the lower extremities. 5,24 Those with more severe complications suffer foot and hand deformities, repeated ankle sprains, intense pain, chronic fatigue, extremely limited ambulatory ability, and distal amputation. 6,10,24,30 Additionally, the psychosocial impact is comparable to patients with stroke and similar impairment. 25 CMT does not appear more frequently in any particular geographical region, age group, race, gender, or ethnic group. 10 It was first described in the late 1880s by three neurologists: Jean Martin Charcot, Pierre Marie, and Howard Henry Tooth. 6,10 During the 50 years following its initial description, many variations of CMT were discovered and described. Yet, it was not until the 1970s and 1980s that scientific and clinical clarity further described and classified CMT. 10 The use of electrophysiology and genetics helped delineate the classifications, as patients with CMT are now grouped by either the results of nerve conduction velocity studies or genetic tests. 5,24 Today, the most conclusive and acceptable confirmation for the presence of CMT disease is accomplished with genetic testing. This applies, however, only to those CMT types and subtypes which currently may be evaluated by genetic assay. No cure exists for CMT, and treatment for CMT traditionally has been focused on limiting impairments caused by the disease process. 5,17,18,24,36 Such intervention historically has included surgical orthodeses (tendon transfers) and prescription of orthotic devices. 5,30 The clinical literature indicates that anklefoot orthoses (AFOs) have been found efficacious in improving physical performance and decreasing the rate of perceived exertion in patients with CMT. 24 Gait training has been found to decrease the amount of energy patients expend while walking, as well as improve stability and strength. 24 Resistance training has been found efficacious in improving strength and activity of daily living (ADL) performance in adults with CMT. 1,7,8,16,18,19,20,22,28,36 13

15 Contemporary Treatment and Management of Charcot-Marie-Tooth Disease Aerobic training has been used to decrease the fatigability and improve the exercise capacity of patients with CMT and other neuromuscular disorders. 11,17 The efficacy of aerobic training over resistance training in CMT patients is somewhat equivocal, primarily because very few systematic basic science investigations exist and, translationally, no clinical trial has directly compared these two exercise modes. Other investigations have examined the use of drugs (e.g., neurotrophin, and prednisone) and nutritional supplements (e.g., ascorbic acid, curcumin, and creatine monohydrate); effectiveness was not demonstrated, or, at best, was uncertain. 5,24 Though no clinical intervention has been standardized to treat CMT, the literature indicates that regular exercise and activity training may, presently, provide the best alternative to manage some of the symptomatology associated with CMT. 1,7,8,11,16,17,18,19,20,22,28,36 LITERATURE SYNOPSIS: THE CASE FOR EXERCISE AND ACTIVITY TRAINING Several forms of intervention have been examined in the treatment of CMT; however, none have proven reliably effective. This includes drugs (e.g., analeptic agents, progesterone antagonists, and neurotrophic factors), nutritional supplements (e.g., ascorbic acid, curcumin, and creatine monohydrate), and surgical procedures (e.g., osteotomy, fasciotomy, tendon transfer, and tendon release). 5,9,24 One type of intervention, exercise, has, however, shown some reliable effectiveness across studies in the treatment and management of CMT. 17,18,36 Though not extensively examined in clinical science, the use of regular exercise and physiotherapy as a treatment for CMT has demonstrated some encouraging results. CMT patients typically have not been referred for exercise or physiotherapy intervention, but the available data indicate that resistance exercise training improves strength, functional outcomes, and morphologic measures in these patients. 1,7,8,16,18,19,20,22,28 A smaller number of studies have demonstrated that different forms of aerobic training may improve aerobic capacity, functional ability, and risk exposure to comorbid disease in CMT patients. 7,8,11 Only a dozen or so studies have examined the use of exercise as a treatment for CMT. Most of these have investigated the use of resistance training in patients with CMT1a. An early study investigating the effects of resistance training established a link between muscular strength and functional ability in patients with CMT. 19 Since then, it has been determined that the traininginduced increase in strength is significantly related to improved ADL performance. 7,8,18 Overall, the literature reveals that resistance training protocols, of at least 12 weeks duration, used in adult CMT populations have proven the most effective. This includes reported beneficial changes in strength, power, functional ability, aerobic capacity, body composition, muscle fiber size, and muscle protein composition. 7,8,18,28 One such investigation examined the effects of low-to-moderate resistance training on aerobic capacity, body composition, muscle fiber type and size, strength, and timed ADLs in 20 CMT patients. 7 Beneficial changes in strength, muscle fiber size and protein composition were observed. Additionally, these muscle adaptations strongly correlated with improved ADLs. 7,8 Though the resistance training did not produce statistically significant improvement in body composition for CMT patients, a clinical change in increased lean mass of 1.5 kg was reported; this was consistent with previous findings of increased lean mass for age-matched healthy persons engaged in similar resistance training programs. 2 Two case-reports have investigated the use of resistance training in children with CMT. A 12-week lower extremity, high-intensity resistance exercise program (up to 80% of one-repetition maximal strength) for a 15-year-old girl with CMT resulted in clinical improvements in plantar flexion and dorsiflexion strength, jumping power, and walking ability. 9 No adverse events or deleterious effects of the trained and associated muscle groups were reported. 9 Another case study, examining the effects of combined moderate-to-moderately-high intensity, resistance, and aerobic training over 1 year in a 16-year-old girl, reported clinical improvements in blood lipids, lean mass, bone mineral density, upper and lower body strength, and several balance measures. The latter included specific beneficial changes in rhythmic weight shift, weightbearing, limits of stability, and sensory interaction on balance (Chetlin, personal communication, This apparently is the only research that has examined both efferent [motor] and afferent [sensory] effects of exercise training in any patients with CMT). The literature indicates that resistance training studies involving CMT patients have used variable amounts of intensity. Though clinical consensus has favored a low-to-moderate intensity approach, based on reported results, resistance training at higher intensities has produced some equivocal results, ranging from no indication of muscle damage to self-reported overuse. 2,18,19,22 Though no study has evaluated the effects of traditional (i.e., continuous) aerobic training or the concurrent effects of resistance and aerobic training in CMT exclusively, when patients engaged in aerobic-type resistance training for 12 weeks, their type I (i.e., oxidative) fibers hypertrophied and their type I myosin heavy chain proteins increased. 7,28 Timed motor performance of functional ability (e.g., chair rise, supine rise, and stair-stepping) and total time of exercise also improved in these patients. A novel finding of this study was that CMT patients are at increased risk for cardiovascular disease due to high body fat percentage and high body mass index (BMI), thus classifying them as obese. 2,7 Seventeen percent of these patients had type 2 diabetes and patients exhibited low exercise capacity, achieving only 5.7 times above resting metabolic equivalents (METS) during graded exercise testing. A peak exercise capacity of 5.7 METS doubles the risk of all-cause mortality compared to individuals with peak capacities of 8 METS or greater. 23 Interestingly, a 24-week program of interval training (i.e., a form of aerobic conditioning, characterized by short, high-intensity bouts interspersed with longer, low-intensity training stanzas) on a bicycle ergometer improved maximal power, lower body isokinetic strength, and timed-motor functional ability in patients with CMT1a and CMT2. 11 Two other important findings were gleaned from this study. First, patients demonstrated the ability to intermittently train at higher intensities (i.e., 1-min bouts at 80% 14

16 Charcot-Marie-Tooth of maximal power and 70-90% of maximum heart rate) without adverse effects. 11 Previous investigations had determined that high-intensity training in the form of resistance exercise may produce overuse/overreach symptoms, while low-to-moderate intensity training would likely avoid such complications. 18 Thus, there might be certain CMT patients who may, without contraindication, exercise at higher levels of exertion. Second, patients improved their maximal oxygen consumption by one MET over the 24-week training period. It is well established that regular aerobic training improves exercise capacity and even a small increase in exercise capacity (i.e., 1 MET) is associated with an 11% reduction in all-cause mortality in both young and old populations. 2,23,29 A 1 MET increase in peak exercise capacity also translates into a 5.4% decrease in healthcare costs associated with a sedentary lifestyle. 35 Considering that combined direct costs of physical inactivity and obesity account for approximately 9.4% of healthcare expenditures in the United States, even small improvements in exercise capacity may translate into substantial healthcare cost reduction in this population. 35 Given that many CMT patients have high BMIs, poor body composition, and poor exercise tolerance, improvements in exercise capacity may reduce risks for coronary artery disease, other comorbidities, and allcause mortality. 7,11,12,14 It would also reduce the cost to treat this group of patients from the effects of a sedentary lifestyle. 35 Despite the established benefits of exercise shown in several studies, the specific question of whether or not individual CMT patients can exercise safely should be addressed. The literature indicates that CMT patients may engage in regular exercise, provided contraindications to exercise are not present. 18,32 These would include known cardiopulmonary disease, poorly controlled diabetes or hypertension, severe orthopedic limitations, and debilitating weakness (i.e., strength levels <15% of normal values). 14,18,32 The latter two are not pure contraindications, because many modes of exercise are likely available to avoid orthopedic complications, and the amount of strength present appears to be related to the expected benefit from the exercise itself. That is, very weak patients may not derive the same magnitude of improvement as those patients who possess more initial strength prior to the commencement of an exercise routine. 18 Additionally, muscle strength appears to be inversely correlated to the histopathology of muscle fibers. 3,7 Therefore, CMT patients, who exhibit the least amount of disruption of their muscle fibers, display greater amounts of strength and may reap greater benefit from an exercise training program. Given that there currently is neither a cure for CMT, nor any standardized treatment protocol to manage the disease, the literature supports the use of regular exercise to improve strength, endurance, and daily function in most CMT patients, as well as reduce their risk of incurring comorbid disease owing to a sedentary lifestyle. Today, allied health practitioners have at their disposal the means to recommend exercise as a scientificallybased clinical intervention to treat patients with chronic disease, including CMT. The goals of clinically-prescribed exercise should focus on improving health, wellness, and quality-of-life through regular physical activity and healthy behaviors. SCIENTIFICALLY-BASED EXERCISE AND ACTIVITY RECOMMENDATIONS FOR CHARCOT- MARIE-TOOTH PATIENTS: THE EXERCISE IS MEDICINE MODEL In 2010, the American College of Sports Medicine hosted the First World Congress for the Exercise Is Medicine (EIM) initiative in Baltimore, Maryland. Together with the recommendations provided by the Physical Activity Guidelines for Americans, published by the United States Department of Health and Human Services, EIM actively promotes these scientifically-based physical activity guidelines to facilitate the important health benefits of exercise and activity for all Americans, including persons with chronic disabilities, such as CMT. 26,32 The clinical aim of EIM is to incorporate activity assessment and exercise prescription, when appropriate, as standard clinical operating procedure in the prevention and treatment of disease. 26 Other organizations, such as the American Medical Association, the United States Department of Health and Human Services, and the Office of the United States Surgeon General, all agree that children and adults with chronic disease and disability (including CMT), whom are capable, should engage in regular forms of activity and exercise. 32 Children with CMT should participate in aerobic, musclestrengthening, bone-strengthening, and balance exercises and activities. Collectively, this should amount to about 1 hour of exercise/activity per day. This should include at least 3 days of moderately vigorous variable activity that is fun, ageappropriate, and not contraindicated for the individual child s medical circumstances. 32 Because CMT is both a motor and sensory neuropathy, it is important to recognize the individual limitations in order to minimize exposure to injury. In most cases, motor control and sensory awareness of the ankle and foot are impaired. Under these circumstances, activities involving running and jumping or other activities where the feet intermittently or continuously leave the ground may not be safe. Alternative exercises and activities should be considered for children with CMT, including bicycle riding (e.g., tandem riding, with the child at the front of the bike and the parent/adult at the back of the bike), games of catching and throwing, swimming, resistance exercises (using the child s own body weight, exercise bands, machines, and hand-held weights), exer-games (video exercise/activity games on the Wii, Playstation, or Xbox game consoles), and lower-intensity martial arts (e.g., tai chi). 32 Additionally, children with CMT should be encouraged as all children should to participate in appropriate forms of play. 32 If children have been prescribed orthopedic braces, these should be worn during exercise and activity where possible. For children with CMT, regular activity, including play, contributes to normal, healthy physical and psychosocial development. 32 Certain clinical evidence indicates that early intervention may attenuate the disease process, possibly contributing to higher levels of function and quality-of-life into adulthood. 32 Additionally, children who adopt an active lifestyle are less likely to be exposed to the eventual dangers of inactivity, including obesity, heart disease, and type 2 diabetes

17 Contemporary Treatment and Management of Charcot-Marie-Tooth Disease Adults with CMT should also participate in various forms of aerobic, muscle-strengthening, bone strengthening, and appropriate balance training. Ideally, it is recommended that adults with CMT should perform about 150 min of total aerobic exercise and activity per week. Such activity should be performed in moderate to moderately vigorous bouts of at least 10 min duration, spread throughout the week. 32 Muscle and bone-strengthening exercises/ activities especially those involving simultaneous use of all major muscle groups should be performed at least 2 days/week. 32 In cases where significant motor and sensory impairment of the ankle and foot are present, exercises and activities where the feet leave the ground, either intermittently or continuously, should not be performed. Some examples of low-impact exercise/activities include riding or rowing exercise, swimming and water aerobics, vigorous gardening (with components like digging and lifting), household chores, resistance exercises (with bands, machines, dumbbells, and/or bodyweight resistance), and low-impact balance and flexibility training (e.g., yoga and tai chi). 32 Though 150 min of total weekly exercise/activity is recommended, adult CMT patients should avoid inactivity; therefore, some physical activity is always better than none. 32 Prescribed orthopedic braces should be worn during exercise and activity where possible. For adults with CMT, regular exercise and activity may improve, or at least maintain, functional ability, independence, and higher quality of life. Like all older adults, an active lifestyle helps to maintain muscle mass and bone health, as well as reducing incidence of falling and avoiding diseases associated with inactivity. 32 FUTURE RESEARCH The vast majority of externally-funded CMT research in the past years has focused on the molecular basis of this heterogeneous group of genetic disorders. During this period, most of this research has used experimental animals, primarily mouse models, to identify a multitude of genes responsible for the diverse mutational mechanisms that cause CMT. To date, 36 loci and at least 24 genes have been implicated in CMT, elucidating mutation, duplication, and deletion phenomena involved in abnormal myelination, axonal transport, Schwann cell differentiation, signal transduction, mitochondrial function, endosomal translation, and DNA repair. 27,30,31 These animal models have been critically important in identifying potential drugs and molecular therapies that may, one day, modify and normalize gene expression in the form of a cure. The logical question that arises from this body of work is, Where do we go from here? Of course, the potential efficacy of drugs and gene therapies must continue to be evaluated at the molecular level using the described animal models, but also a fully translational and bi-directional paradigm (re: bench-to-bedsideto-bench ) must be developed that not only satisfies the scientific community but also creates optimism in the CMT community, including patients and their families. Furthermore, such a process must allow for refinement and adjustment of the exercise model as a more integrated understanding of the basic science, clinical evaluation, and patient feedback becomes available. There exists a palpable frustration amongst patients today that the scientific community has become so enamored with the molecular dialectic 16 that direct intervention or treatment for patients currently has been relegated to a lower tier of importance (Chetlin, personal communications, 2007, 2011). Given that the body of evidence that exercise and physical activity has produced promising results across studies and clinical populations, perhaps such regimens should be given careful consideration as part of a fully translational model in CMT research. Exercise has been used effectively in several clinical circumstances, including, for example, treatment for type 2 diabetes, cardiac rehabilitation, hypertension, cancer, orthopedic rehabilitation, and the neuromuscular syndrome associated with aging. 26 Furthermore, appropriate exercise prescription has been shown to improve patient sensitivity to various drugs, thus demonstrating a permissive effect between regular exercise and specific pharmaceutical agents, such as cardiac (e.g., cardiac glycosides and nitroglycerin), antihypertensive (e.g., ACE inhibitors and calcium channel blockers), and hypoglycemic (e.g., insulin and sulfonylureas) medications. 15,21 The interventional redundancy associated with exercise a demonstration of effectiveness across clinical populations is not surprising. Acute and chronic physical activity is associated with systemic upregulation, including biochemical, hormonal, physiologic, and molecular responsiveness. 2,14 These beneficial effects have been recognized, of course, in the EIM model, a nearuniversal clinical intervention endorsed by the American Medical Association, American College of Sports Medicine, and the Office of the Surgeon General. 26 The spectrum of desirable exercise effects has been classically observed, for example, in the treatment of type 2 diabetes; a disease with multiple hallmarks, including diabetic neuropathy. Patients who exercise not only become more sensitive to their hypoglycemic drugs, but exercise alone is considered insulin-mimetic; most compliant patients, who adhere to their exercise prescription and dietary modifications, eventually do not require drugs to combat this metabolic disorder. 33 If exercise has demonstrated effectiveness in a multitude of animal and human models associated with multiple clinical conditions, then why has it not been more extensively examined in the treatment of other diseases, such as CMT? How may it be possible to know if exercise, combined with drugs or genetic therapies, may promote an additive effect greater than either the drug or exercise effects alone? The answers to these questions should serve as the foundation to include an additional arm to the present CMT research direction. The mouse models are, of course, extremely important; these studies not only reveal the genes responsible for CMT, but they can help to identify those molecular and biological mechanisms resulting in pharmaceutical and gene therapies to treat this disease. These models should, however, be complemented by a fully translational component that includes aerobic, resistance, and combined exercise. This initially may take the form of rodents exercising on treadmills, dynamometers, or both with and without the potentially effective drugs and gene therapies identified by way of the mouse models. Part of such a process would include identifying those outcomes of localization, distribution, quantification, and performance that could be carried over to human trials. This approach, or one similar to it, if

18 Charcot-Marie-Tooth supported by government, foundation, and other funding entities, would give patients what they presently desire most: results they can personally identify with and the hope a very real and personal hope that one day, in the not-so-distant future, a cure for CMT ultimately will be discovered. REFERENCES 1. Aitkens S, McCrory M, Kilmer D, Bernauer E. Moderate resistance exercise program: its effect in slowly progressive neuromuscular disease. Arch Phys Med Rehabil 1993;74: Balady G, Berra M, Golding L, Gordon N, Mahler D, Myers J, Sheldahl L. Physical fitness testing and interpretation. In: Franklin B, ed. ACSM s guidelines for exercise testing and prescription, 6th ed. Philadelphia: Lipincott, Williams & Wilkins; pp Borg K, Ericson-Gripenstedt. Muscle biopsy abnormalities differ between Charcot-Marie-Tooth type 1 and 2: reflect different pathophysiology? Exerc Sport Sci Rev 2002;30: Burns J, Raymond J, Ouvrier R. Feasibility of foot and ankle strength training in childhood Charcto-Marie-Tooth disease. Neuromuscul Disord 2009;19: Carter G, Weiss M, Han J, Chance P, England J. Charcot-Marie- Tooth disease. Curr Treat Options Neurol 2008;10: Chance P, Pleasure D. Charcot-Marie-Tooth syndrome. Arch Neurol 1993;50: Chetlin R, Gutmann L, Tarnopolsky M, Ullrich I, Yeater R. Resistance training exercise and creatine in patients with Charcot- Marie-Tooth disease. Muscle Nerve 2004;30: Chetlin R, Gutmann L, Tarnopolsky M, Ullrich I, Yeater R. Resistance training effectiveness in patients with Charcot-Marie- Tooth disease: recommendations for exercise prescription. Arch Phys Med Rehabil 2004;85: de Visser M, Verhamme C. Ascorbic acid treatment in CMT1A: what s next? Lancet Neurol 2011;10: Dyck P, Chance P, Lebo R, Carney J. Hereditary motor and sensory neuropathies. In: Dyck P, Thomas P, eds. Peripheral Neuropathy, 3rd ed. Philadelphia: WB Saunders; pp El Mhandi L, Millet G, Calmels P, Richard A, Oullion R, Gautheron V, Feasson L. Benefits of interval training on fatigue and functional capacities in Charcot-Marie-Tooth disease. Muscle Nerve 2008;37: Gordon N, Leighton R, Mooss A. Factors associated with increased risk of coronary heart disease. In: Kaminsky L, ed. ACSM s resource manual for guidelines for exercise testing and prescription, 5th ed. Philadelphia: Lipincott, Williams & Wilkins; pp Hanemann C, Muller H. Pathogenesis of Charcot-Marie-Tooth IA (CMTIA) neuropathy. Trends Neurosci 1998;21: Katzmarzyk P. Physical activity status and chronic diseases. In: Kaminsky L, ed. ACSM s resource manual for guidelines for exercise testing and prescription, 5th ed. Philadelphia: Lipincott, Williams & Wilkins; pp Khazaeinia T, Ramsey A, Tam Y. The effects of exercise on the pharmacokinetics of drugs. J Pharm Pharmaceut Sci 2000;3: Kilmer D, McCrory M, Wright N, Aitkens S, Bernauer E. The effect of a high resistance exercise program in slowly progressive neuromuscular disease. Arch Phys Med Rehabil 1994;75: Kilmer D. Response to aerobic exercise training in humans with neuromuscular disease. Am J Phys Med Rehabil 2002;81:S148- S Kilmer D. Response to resistive strengthening exercise training in humans with neuromuscular disease. Am J Phys Med Rehabil 2002;81:S Lindeman E, Leffers P, Reulen J, Spaans F, Drukker J. Quadriceps strength and timed motor performances in myotonic dystrophy, Charcot-Marie-Tooth disease, and healthy subjects. Clin Rehabil 1998;12: Lindeman E, Leffers P, Spaans F, Drukker J, Reulen J, Kerckhoffs M, Koke A. Strength training in patients with myotonic dystrophy and hereditary motor and sensory neuropathy: a randomized clinical trial. Arch Phys Med Rehabil 1995;76: Lowenthal D, Kendrick Z. Drug-exercise interactions. Ann Rev Pharmacol Toxicol 1985;25: Milner-Brown H, Miller R. Muscle strengthening through highresistance weight training in patients with neuromuscular disorders. Arch Phys Med Rehabil 1988;69: Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood J. Exercise capacity and mortality among men referred for exercise testing. N Eng J Med 2002;346(11): Pareyson D, Marchesi, C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol 2009;8: Pfeiffer G, Wicklein E, Ratusinski T, Schmitt L, Kunze K. Disability and quality of life in Charcot-Marie-Tooth disease type I. J Neurol Neurosurg Psychiatry 2001;70: Sallis RE. Exercise is medicine and physicians need to prescribe it. Br J Sports Med 2009;43: Sereda M, Nave K. Animal models of Charcot-Marie-Tooth disease type 1A. Neuromol Med 2006;8: Smith C, Chetlin R, Gutmann L, Yeater R, Alway S. Effects of exercise and creatine on myosin heavy chain isoform composition in patients with Charcot-Marie-Tooth disease. Muscle Nerve 2006;34: Spin J, Prakash M, Froelicher V, Parrington S, Marcus R, Do D, Myers J. The prognostic value of exercise testing in elderly men. Am J Med 2002;112: Szigeti K, Lupski J. Charcot-Marie-Tooth disease. Eur J Human Genetics 2009;17: Tanaka Y, Hirokawa N. Mouse models of Charcot-Marie-Tooth disease. Trend Genet 2002;18:S39-S United States Physical activity guidelines for Americans ( Washington: USHHS; Verity L. Exercise prescription in patients with diabetes. In: Ehrman J, ed. ACSM s Resource manual for guidelines for exercise testing and prescription, 6th ed. Philadelphia: Lipincott, Williams & Wilkins; pp Vinci P, Esposito C, Perelli SL, Antenor JA, Thomas FP. Overwork weakness in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil 2003;84: Weiss J, Froelicher V, Myers J, Heidenreich P. Exercise and the heart: health-care costs and exercise capacity. Chest 2004;126: Young P, De Jonghe P, Stogbauer F, Butterfass-Bahlooul T. Treatment for Charcot-Marie-Tooth disease. 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20 Corrective Lower Limb Bracing in Charcot-Marie-Tooth Disease Mitchell Warner, CPO Certified Prosthetist and Orthotist Ortho Rehab Designs Prosthetics and Orthotics Inc. Las Vegas, Nevada INTRODUCTION Charcot-Marie-Tooth (CMT) disease presents with a complicated combination of lower limb deformities, muscle weakness, and balance loss. It is important to take these under consideration when developing a treatment plan that involves prescribing lower limb orthoses. Although CMT is genetic, there usually are marked differences between affected family members. They can be affected at different ages and with varying severity of symptoms. For this reason, each individual that presents with CMT is unique and should be treated as such. SYMPTOMS CMT symptoms may include the following: Foot drop: This occurs when the forefoot drags and fails to clear the floor. The patient may compensate by exaggerated hip and knee flexion. 1 This occurs due to lack of dorsiflexion control. This can be noted with a side view observation of the patient. The foot drops to the floor at the beginning of the stance phase and during swing phase. Pes cavus deformity: This is an unduly high arch, an exaggeration of the normal longitudinal arch of the foot. 2 Varus deformities: These deformities are present when the angulation of the body part is toward the midline of the body (bent inward). 2 Deformities occur at the subtalar joint. The patient walks on the lateral border of the foot. The subtalar alignment in varus is in the position of supination and adduction. Valgus deformities: These deformities are present when the angulation of the body part is away from the midline of the body (bent outward, twisted). 3 Deformities occur at the subtalar joint. The patient walks on the medial border of the foot. The subtalar axis moves in the position of pronation and abduction. This is best observed from the front and back of the patient. Muscle atrophy: This is wasting of muscle tissue. Balance loss: This can be observed when the patient is constantly moving their feet or using excessive knee flexion in order to lower their center of gravity for stability. Factors that contribute to balance loss in CMT include loss of sensory feedback, muscular weakness, and neuropathy. ANALYSIS OF PATHOLOGICAL GAIT Systematic analysis is a valuable clinical tool for determining the nature and severity of the patient s skeletal or neuromuscular deviations/deficiencies. This also helps assess the adequacy of orthoses and other aids intended to assist in achieving a more normal ambulation. 5 Many gait deviations are created by the neuromuscular patterns produced from CMT. These are a result of nerve loss, muscular weakness, and ligamentous laxity. This almost always results in a reduction of normal walking speed. Some of the more difficult gait deviations that occur include: Hip hiking (Fig. 1) Circumduction Internal or external limb rotation Abnormal walking base Lateral trunk bending Hyperextended knee Excessive knee flexion Insufficient toe off 19

21 Corrective Lower Limb Bracing in Charcot-Marie-Tooth Disease Figure 1. An example of hip hiking and foot drop. Figure 2. An example of pes cavus. DETERMINING THE CORRECT TYPE OF ORTHOSIS Selecting the Appropriate Device for the CharcotMarie-Tooth Patient Ankle-Foot Orthosis Versus Knee-Ankle-Foot Orthosis Factors used when determining and prescribing a lower limb orthosis include age; overall strength; hand involvement;quadriceps strength; tibialis anterior strength; gastrocnemius strength; extent of damage to muscles, tendons, ligaments, bones, and joints; as well as balance. Ankle-Foot Orthosis An ankle-foot orthosis (AFO) is any orthotic device for the lower limb that encloses the ankle and foot and does not extend above the knee and is intended to prevent a foot from dropping due to inadequate dorsiflexion. Knee-Ankle-Foot Orthosis A knee-ankle-foot orthosis (KAFO) is any orthotic device for the lower limb that extends from above the knee to the ankle and foot. A KAFO would be used with a patient with a foot drop as well as a weak quadriceps that prevents the patient from being able to control knee flexion. Another consideration for a KAFO would be knee hyperextension greater than 15 degrees that cannot be controlled below the knee. Variations of Ankle-Foot Orthoses and KneeAnkle-Foot Orthoses The current types of lower limb orthoses for foot drop include off the shelf models that come in small, medium, and large for both the left and right feet as well as custom made models that are fabricated from a mold of the patient s lower limb that enables an exact fit with patient-specific corrections to the joints. The various mechanical types include posterior leaf spring, jointed, solid ankle, floor reaction, and energy-storing (Helios type). The materials used include: metal, leather, thermoplastics, carbon fiber, and composites. 20 Most CMT patients have similar symptoms, but their deformities and muscular weakness manifest in a myriad of ways. To determine the primary muscles that are affected due to the neuropathy, manual muscle testing to perform during a patient s evaluation. This will help determine what type of brace would best serve the individual CMT patient. FOOT DROP Foot drop is a result of a neuropathy of the deep peroneal nerve which then does not send a signal to the tibialis anterior to dorsiflex the foot. Most people affected complain that when they walk their toes catch the ground and they trip and fall. Gastrocnemius weakness is also associated with this. Patients with gastrocnemius weakness cannot plantar flex, and this affects their gait. When walking, they cannot push off the ground to initiate the swing phase. Thus, the most common symptoms affecting walking seen in CMT patients are tibialis anterior weakness and gastrocnemius weakness. General muscle atrophy is also seen. The most common deformity seen among all CMT patients is pes cavus5 (Fig. 2). The other two primary deformities seen in CMT patients are varus and valgus. Although there are no correlations of studies on this, it is the author s experience that most patients with CMT1 fall into a varus angulation and most patients with CMT 2 fall into a valgus deformity. BALANCE LOSS The most common symptom experience by all CMT patients is balance loss. They rely on leaning on objects while standing. They always ask if there is a brace that can help them restore their balance; however, this is not possible. But, better balance can be achieved through proper bracing and corrections. CMT patients also have a high degree of fatigue that sets in after walking for short periods. They have a balance loss combined with a foot drop and a possible varus or valgus deformity that is rotating